Views
5 years ago

A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

• Discovery • •

• Discovery • • Screening Preclinical testing Early (exploratory) development • Phase I (usually healthy volunteers) Proof of principle • Phase IIa Proof of concept • Phase IIb • Phase III (1000–5000 patients) * Registration Late (confirmatory) development • Phase IV Cost is approximately £500 million, 60% of which is spent in clinical trials. Time from discovery to registration approximately 10–13 years Figure 15.1: Stages of drug development. of practice, namely Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP) and Good Clinical Practice (GCP). Good Clinical Practice is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. The stages of drug development are outlined in Figure 15.1. DRUG DISCOVERY, DESIGN AND SYNTHESIS Whilst random screening and serendipity remain important in the discovery of new drugs, new knowledge of the role of receptors, enzymes, ion channels and carrier molecules in both normal physiological processes and disease now permits a more focused approach to drug design. Using advances in combinatorial chemistry, biotechnology, genomics, high output screening and computer-aided drug design, new drugs can now be identified more rationally. PRECLINICAL STUDIES New chemical entities are tested in animals to investigate their pharmacology, toxicology, pharmacokinetics and potential efficacy in order to select drugs of potential value in humans. Although there is considerable controversy concerning the value of some studies performed in animals, human drug development has an excellent safety record, and there is understandable reluctance on the part of the regulatory authorities to reduce requirements. At present, the European guidelines require that the effects of the drug should be assessed in two mammalian species (one non-rodent) after two weeks of dosing before a single dose is administered to a human. In addition, safety pharmacology and mutagenicity tests will have been assessed. Additional and longer duration studies are conducted before product licence approval. The timing, specific tests and duration of studies may relate to the proposed human usage in both the clinical trials and eventual indications. CLINICAL TRIALS CLINICAL TRIALS 87 Physicians read clinical papers, review articles and pharmaceutical advertisements describing clinical trial results. Despite peer review, the incompetent or unscrupulous author can conceal deficiencies in design and possibly publish misleading data. The major medical journals are well refereed, although supplements to many medical journals are less rigorously reviewed for scientific value. An understanding of the essential elements of clinical trial design enables a more informed interpretation of published data. Assessment of a new treatment by clinical impression is not adequate. Diseases may resolve or relapse spontaneously, coincidental factors may confound interpretation, and the power of placebo and enthusiastic investigators are a major influence on subjective response. In order to minimize these factors and eliminate bias, any new treatment should be rigorously assessed by carefully designed, controlled clinical trials. All physicians involved in clinical trials must follow the guidelines of the Declaration of Helsinki and subsequent amendments. OBJECTIVES The first step in clinical trial design is to determine the questions to be addressed. Primary and achievable objectives must be defined. The question may be straightforward. For example, does treatment A prolong survival in comparison with treatment B following diagnosis of small-cell carcinoma of the lung? Survival is a clear and objective end-point. Less easily measured end-points such as quality of life must also be assessed as objectively as possible. Prespecified subgroups of patients may be identified and differences in response determined. For example, treatment A may be found to be most effective in those patients with limited disease at diagnosis, whereas treatment B may be most effective in those with widespread disease at diagnosis. Any physician conducting a clinical trial must not forget that the ultimate objective of all studies is to benefit patients. The patients’ welfare must be of paramount importance. RANDOMIZATION Patients who agree to enter such a study must be randomized so that there is an equal likelihood of receiving treatment A or B. If treatment is not truly randomized, then bias will occur. For example, the investigator might consider treatment B to be less well tolerated and thus decide to treat particularly frail patients with treatment A. Multicentre studies are often necessary in order to recruit adequate numbers of patients, and it is essential to ensure that the treatments are fairly compared. If treatment A is confined to one centre/hospital and treatment B to another, many factors may affect the outcome of the study due to differences between the centres, such as interval

88 INTRODUCTION OF NEW DRUGS AND CLINICAL TRIALS between diagnosis and treatment, individual differences in determining entry criteria, facilities for treatment of complications, differing attitude to pain control, ease of transport, etc. INCLUSION AND EXCLUSION CRITERIA For any study, inclusion and exclusion criteria must be defined. It is essential to maximize safety and minimize confounding factors, whilst also ensuring that the criteria are not so strict that the findings will be applicable only to an unrepresentative subset of the patient population encountered in usual practice. The definition of a healthy elderly subject is problematic. Over the age of 65 years, it is ‘normal’ (in the sense that it is common) to have a reduced creatinine clearance, to be on some concomitant medication and to have a history of allergy. If these are exclusion criteria, a trial will address a ‘superfit’ elderly population and not a normal population. DOUBLE-BLIND DESIGN A ‘double-blind’ design is often desirable to eliminate psychological factors such as enthusiasm for the ‘new’ remedy. This is not always possible. For example, if in the comparison of treatment A and treatment B described above, treatment A consists of regular intravenous infusions whilst treatment B consists of oral medication, the ‘blind’ is broken. As ‘survival’ duration is ‘hard’ objective data, this should not be influenced markedly, whereas softer end-points, such as the state of wellbeing, are more easily confounded. In trials where these are especially important, it may be appropriate to use more elaborate strategies to permit blinding, such as the use of a ‘double dummy’ where there is a placebo for both dosage forms. In this case patients are randomized to active tablets plus placebo infusion or to active infusion plus placebo tablets. WITHDRAWALS The number of patients who are withdrawn from each treatment and the reason for withdrawal (subjective, objective or logistic) must be taken into account. For example, if in an antihypertensive study comparing two treatments administered for three months only the data from those who completed three months of therapy with treatment X or Y are analysed, this may suggest that both treatments were equally effective. However, if 50% of the patients on treatment X withdrew after one week because of lack of efficacy, that conclusion is erroneous. Again, if patients are withdrawn after randomization but before dosing, this can lead to unrecognized bias if more patients in one group die before treatment is started than in the other group, leading to one group containing a higher proportion of fitter ‘survivors’. Conversely, if patients are withdrawn after randomization but before dosing, adverse events cannot be attributed to the drug. Hence both an ‘intention-to-treat’ analysis and a ‘treatment-received’ analysis should be presented. PLACEBO If a placebo control is ethical and practical, this simplifies interpretation of trial data and enables efficacy to be determined more easily (and with much smaller numbers of subjects) than if an effective active comparator is current standard treatment (and hence ethically essential). It is well recognized that placebo treatment can have marked effects (e.g. lowering of blood pressure). This is partly due to patient familiarization with study procedures, whose effect can be minimized by a placebo ‘run-in’ phase. TRIAL DESIGN There is no one perfect design for comparing treatments. Studies should be prospective, randomized, double-blind and placebo-controlled whenever possible. Parallel-group studies are those in which patients are randomized to receive different treatments. Although tempting, the use of historical data as a control is often misleading and should only be employed in exceptional circumstances. Usually one of the treatments is the standard, established treatment of choice, i.e. the control, whilst the other is an alternative – often a new treatment which is a potential advance. In chronic stable diseases, a crossover design in which each subject acts as his or her own control can be employed. Intra-individual variability in response is usually much less than inter-individual variability. The treatment sequence must be evenly balanced to avoid order effects and there must be adequate ‘washout’ to prevent a carry-over effect from the first treatment. This design is theoretically more ‘economical’ in subject numbers, but is often not applicable in practice. STATISTICS It is important to discuss the design and sample size of any clinical trial with a statistician at the planning phase. Research papers often quote P values as a measure of whether or not an observed difference is ‘significant’. Conventionally, the null hypothesis is often rejected if P � 0.05 (i.e. a difference of the magnitude observed would be expected to occur by chance in less than one in 20 trials – so-called type I error, see Figure 15.2). This is of limited value, as a clinically important difference may be missed if the sample size is too small (type II error, see Figure 15.2). To place reliance on a negative result, the statistical power of the study should be at least �0.8 and preferably �0.9 (i.e. a true difference of the magnitude prespecified would be missed in 20% or 10% of such trials, respectively). It is possible to calculate the number of patients required to establish a given difference between treatments at a specified level of statistical confidence. For a continuous variable, one needs an estimate of the mean and standard deviation which one would expect in the control group. This is usually available from historical data, but a pilot study may be necessary. The degree of uncertainty surrounding observed

  • Page 2 and 3:

    A Textbook of Clinical Pharmacology

  • Page 4 and 5:

    A Textbook of Clinical Pharmacology

  • Page 6 and 7:

    This fifth edition is dedicated to

  • Page 8 and 9:

    FOREWORD viii PREFACE ix ACKNOWLEDG

  • Page 10 and 11:

    PREFACE Clinical pharmacology is th

  • Page 12 and 13:

    PART I GENERAL PRINCIPLES

  • Page 14 and 15:

    ● Use of drugs 3 ● Adverse effe

  • Page 16 and 17:

    and acquired factors, notably disea

  • Page 18 and 19:

    100 Effect (%) 0 0 5 10 1 10 100 (a

  • Page 20 and 21:

    Dose ratio -1 100 50 The relationsh

  • Page 22 and 23:

    ● Introduction 11 ● Constant-ra

  • Page 24 and 25:

    In reality, processes of eliminatio

  • Page 26 and 27:

    lood (from which samples are taken

  • Page 28 and 29:

    ● Introduction 17 ● Bioavailabi

  • Page 30 and 31:

    ROUTES OF ADMINISTRATION ORAL ROUTE

  • Page 32 and 33:

    Transdermal absorption is sufficien

  • Page 34 and 35:

    FURTHER READING Fix JA. Strategies

  • Page 36 and 37:

    and thromboxanes are CYP450 enzymes

  • Page 38 and 39:

    and lorazepam. Some patients inheri

  • Page 40 and 41:

    Orally administered drug Parenteral

  • Page 42 and 43:

    ● Introduction 31 ● Glomerular

  • Page 44 and 45:

    ACTIVE TUBULAR REABSORPTION This is

  • Page 46 and 47:

    DISTRIBUTION Drug distribution is a

  • Page 48 and 49: Detailed recommendations on dosage
  • Page 50 and 51: DIGOXIN Myxoedematous patients are
  • Page 52 and 53: ● Introduction 41 ● Role of dru
  • Page 54 and 55: 25 20 10 Life-threatening toxicity
  • Page 56 and 57: ● Introduction 45 ● Harmful eff
  • Page 58 and 59: vagina in girls in their late teens
  • Page 60 and 61: an anti-analgesic effect when combi
  • Page 62 and 63: Case history A 20-year-old female m
  • Page 64 and 65: METABOLISM At birth, the hepatic mi
  • Page 66 and 67: lifelong effects as a result of tox
  • Page 68 and 69: DISTRIBUTION Ageing is associated w
  • Page 70 and 71: DIGOXIN Digoxin toxicity is common
  • Page 72 and 73: FURTHER READING Dhesi JK, Allain TJ
  • Page 74 and 75: Factors involved in the aetiology o
  • Page 76 and 77: analgesic. Following its release, t
  • Page 78 and 79: antibiotics, such as penicillin or
  • Page 80 and 81: predisposes to non-immune haemolysi
  • Page 82 and 83: ● Introduction 71 ● Useful inte
  • Page 84 and 85: Response Therapeutic range Toxic ra
  • Page 86 and 87: Table 13.1: Interactions outside th
  • Page 88 and 89: Table 13.5: Competitive interaction
  • Page 90 and 91: ● Introduction: ‘personalized m
  • Page 92 and 93: Table 14.2: Variations in drug resp
  • Page 94 and 95: lipoprotein (LDL) is impaired. LDL
  • Page 96 and 97: Key points • Genetic differences
  • Page 100 and 101: Too many statistical comparisons pe
  • Page 102 and 103: ETHICS COMMITTEES Protocols for all
  • Page 104 and 105: Table 16.1: Recombinant proteins/en
  • Page 106 and 107: duration and benefit. Adenoviral ve
  • Page 108 and 109: ● Introduction 97 ● Garlic 97
  • Page 110 and 111: A case report has suggested a possi
  • Page 112 and 113: including hypericin and pseudohyper
  • Page 114 and 115: PART II THE NERVOUS SYSTEM
  • Page 116 and 117: ● Introduction 105 ● Sleep diff
  • Page 118 and 119: and daytime sleeping should be disc
  • Page 120 and 121: Key points • Insomnia and anxiety
  • Page 122 and 123: Box 19.1: Dopamine theory of schizo
  • Page 124 and 125: The Boston Collaborative Survey ind
  • Page 126 and 127: Oral medication, especially in liqu
  • Page 128 and 129: e.g. interpersonal difficulties or
  • Page 130 and 131: Partial response to first-line trea
  • Page 132 and 133: Key points Drug treatment of depres
  • Page 134 and 135: Case history A 45-year-old man with
  • Page 136 and 137: Levodopa PRINCIPLES OF TREATMENT IN
  • Page 138 and 139: • pulmonary, retroperitoneal and
  • Page 140 and 141: CHOREA The γ-aminobutyric acid con
  • Page 142 and 143: Cholinergic crisis Treatment of mya
  • Page 144 and 145: ● Introduction 133 ● Mechanisms
  • Page 146 and 147: absolute arbiter. The availability
  • Page 148 and 149:

    Table 22.2: Metabolic interactions

  • Page 150 and 151:

    FURTHER ANTI-EPILEPTICS Other drugs

  • Page 152 and 153:

    Case history A 24-year-old woman wh

  • Page 154 and 155:

    Assessment of migraine severity and

  • Page 156 and 157:

    ● General anaesthetics 145 ● In

  • Page 158 and 159:

    is the theoretical concern of a ‘

  • Page 160 and 161:

    • Respiratory system - apnoea fol

  • Page 162 and 163:

    Competitive antagonists (vecuronium

  • Page 164 and 165:

    have also proved useful in combinat

  • Page 166 and 167:

    ● Introduction 155 ● Pathophysi

  • Page 168 and 169:

    ASPIRIN (ACETYLSALICYLATE) Use Anti

  • Page 170 and 171:

    Key points Drugs for mild pain •

  • Page 172 and 173:

    increases, correlating with the hig

  • Page 174 and 175:

    • If possible, use oral medicatio

  • Page 176 and 177:

    PART III THE MUSCULOSKELETAL SYSTEM

  • Page 178 and 179:

    ● Introduction: inflammation 167

  • Page 180 and 181:

    Chapter 33). All NSAIDs cause wheez

  • Page 182 and 183:

    • Stomatitis suggests the possibi

  • Page 184 and 185:

    Pharmacokinetics Allopurinol is wel

  • Page 186 and 187:

    PART IV THE CARDIOVASCULAR SYSTEM

  • Page 188 and 189:

    ● Introduction 177 ● Pathophysi

  • Page 190 and 191:

    esponsible for the strong predilect

  • Page 192 and 193:

    Ezetimibe Fat Muscle Dietary fat In

  • Page 194 and 195:

    educed). The risk of muscle damage

  • Page 196 and 197:

    ● Introduction 185 ● Pathophysi

  • Page 198 and 199:

    Each of these classes of drug reduc

  • Page 200 and 201:

    AT 1 receptor) produce good 24-hour

  • Page 202 and 203:

    Table 28.2: Examples of calcium-cha

  • Page 204 and 205:

    Key points Drugs used in essential

  • Page 206 and 207:

    Case history A 72-year-old woman se

  • Page 208 and 209:

    Assess risk factors Investigations:

  • Page 210 and 211:

    Persistent ST segment elevation Thr

  • Page 212 and 213:

    Mechanism of action GTN works by re

  • Page 214 and 215:

    Because of the risks of haemorrhage

  • Page 216 and 217:

    Intrinsic pathway XIIa XIa the acti

  • Page 218 and 219:

    that the pharmacodynamic response i

  • Page 220 and 221:

    used with apparent benefit in acute

  • Page 222 and 223:

    ● Introduction 211 ● Pathophysi

  • Page 224 and 225:

    The drugs that are most effective i

  • Page 226 and 227:

    therapeutic plasma concentration ca

  • Page 228 and 229:

    ● Common dysrhythmias 217 ● Gen

  • Page 230 and 231:

    BASIC LIFE SUPPORT CARDIOPULMONARY

  • Page 232 and 233:

    arrest. The electrocardiogram is li

  • Page 234 and 235:

    should be given to insertion of an

  • Page 236 and 237:

    Drug interactions Amiodarone potent

  • Page 238 and 239:

    effect when treating sinus bradycar

  • Page 240 and 241:

    Case history A 24-year-old medical

  • Page 242 and 243:

    PART V THE RESPIRATORY SYSTEM

  • Page 244 and 245:

    CHAPTER 33 THERAPY OF ASTHMA, CHRON

  • Page 246 and 247:

    STEP 5: CONTINUOUS OR FREQUENT USE

  • Page 248 and 249:

    Adenylyl cyclase Table 33.1: Compar

  • Page 250 and 251:

    Drug interactions Although synergis

  • Page 252 and 253:

    use in asthma has declined consider

  • Page 254 and 255:

    α 1-antitrypsin deficiency, neutro

  • Page 256 and 257:

    PART VI THE ALIMENTARY SYSTEM

  • Page 258 and 259:

    ● Peptic ulceration 247 ● Oesop

  • Page 260 and 261:

    PEPTIC ULCERATION 249 • With rega

  • Page 262 and 263:

    Ranitidine has a similar profile of

  • Page 264 and 265:

    Vestibular stimulation ? via cerebe

  • Page 266 and 267:

    cortical centres affecting vomiting

  • Page 268 and 269:

    • in hepatocellular failure to re

  • Page 270 and 271:

    Ciprofloxacin is occasionally used

  • Page 272 and 273:

    withdrawal), small doses of benzodi

  • Page 274 and 275:

    Table 34.7: Dose-independent hepato

  • Page 276 and 277:

    ● Introduction 265 ● General ph

  • Page 278 and 279:

    dinucleotide (NAD) and nicotinamide

  • Page 280 and 281:

    Table 35.1: Common trace element de

  • Page 282 and 283:

    PART VII FLUIDS AND ELECTROLYTES

  • Page 284 and 285:

    ● Introduction 273 ● Volume ove

  • Page 286 and 287:

    Key points Diuretics Diuretics are

  • Page 288 and 289:

    is sometimes caused by drugs, notab

  • Page 290 and 291:

    or with potassium-sparing diuretics

  • Page 292 and 293:

    Greger R, Lang F, Sebekova, Heidlan

  • Page 294 and 295:

    PART VIII THE ENDOCRINE SYSTEM

  • Page 296 and 297:

    ● Introduction 285 ● Pathophysi

  • Page 298 and 299:

    in prefilled injection devices (‘

  • Page 300 and 301:

    Metformin should be withdrawn and i

  • Page 302 and 303:

    FURTHER READING American Diabetes A

  • Page 304 and 305:

    deficiency. Potassium iodide (3 mg

  • Page 306 and 307:

    fertility. It is contraindicated du

  • Page 308 and 309:

    ● Introduction 297 ● Vitamin D

  • Page 310 and 311:

    effective in life-threatening hyper

  • Page 312 and 313:

    Further reading Block GA, Martin KJ

  • Page 314 and 315:

    Table 40.1: Actions of cortisol and

  • Page 316 and 317:

    injection may be useful, but if don

  • Page 318 and 319:

    CHAPTER 41 REPRODUCTIVE ENDOCRINOLO

  • Page 320 and 321:

    elease by the pituitary via negativ

  • Page 322 and 323:

    Treatment with depot progestogen in

  • Page 324 and 325:

    infusion using an infusion pump to

  • Page 326 and 327:

    significant proportion of men who r

  • Page 328 and 329:

    with symptoms caused by the release

  • Page 330 and 331:

    FURTHER READING Birnbaumer M. Vasop

  • Page 332 and 333:

    PART IX SELECTIVE TOXICITY

  • Page 334 and 335:

    ● Principles of antibacterial che

  • Page 336 and 337:

    2. transfer of resistance between o

  • Page 338 and 339:

    Pharmacokinetics Absorption of thes

  • Page 340 and 341:

    Mechanism of action Macrolides bind

  • Page 342 and 343:

    asic quinolone structure dramatical

  • Page 344 and 345:

    Case history A 70-year-old man with

  • Page 346 and 347:

    PRINCIPLES OF MANAGEMENT OF MYCOBAC

  • Page 348 and 349:

    Pharmacokinetics Absorption from th

  • Page 350 and 351:

    MYCOBACTERIUM LEPRAE INFECTION Lepr

  • Page 352 and 353:

    POLYENES AMPHOTERICIN B Uses Amphot

  • Page 354 and 355:

    therapy is adequate though more fre

  • Page 356 and 357:

    NUCLEOSIDE ANALOGUES ACICLOVIR Uses

  • Page 358 and 359:

    Table 45.3: Summary of available ac

  • Page 360 and 361:

    Uses Interferon-α when combined wi

  • Page 362 and 363:

    ● Introduction 351 ● Immunopath

  • Page 364 and 365:

    Table 46.1: Examples of combination

  • Page 366 and 367:

    NON-NUCLEOSIDE ANALOGUE REVERSE TRA

  • Page 368 and 369:

    FUSION INHIBITORS Uses Currently, e

  • Page 370 and 371:

    salvage therapy include azithromyci

  • Page 372 and 373:

    ● Malaria 361 ● Trypanosomal in

  • Page 374 and 375:

    Pharmacokinetics Chloroquine is rap

  • Page 376 and 377:

    Table 47.2: Drug therapy of non-mal

  • Page 378 and 379:

    ● Introduction 367 ● Pathophysi

  • Page 380 and 381:

    Table 48.1: Classification of commo

  • Page 382 and 383:

    Polymorph count/mm 3 (a) (b) 10 000

  • Page 384 and 385:

    doses are used to prepare patients

  • Page 386 and 387:

    Adverse effects Methotrexate Inhibi

  • Page 388 and 389:

    Table 48.7: Summary of clinical pha

  • Page 390 and 391:

    Table 48.9: Summary of the clinical

  • Page 392 and 393:

    Plasma membrane Signal transduction

  • Page 394 and 395:

    Table 48.10: Monoclonal antibodies

  • Page 396 and 397:

    INTERFERON-ALFA 2B Interferon-alfa

  • Page 398 and 399:

    PART X HAEMATOLOGY

  • Page 400 and 401:

    ● Haematinics - iron, vitamin B 1

  • Page 402 and 403:

    one marrow to produce red cells. Th

  • Page 404 and 405:

    EPO Erythroid precursors Erythrocyt

  • Page 406 and 407:

    Therapeutic principles The extent o

  • Page 408 and 409:

    PART XI IMMUNOPHARMACOLOGY

  • Page 410 and 411:

    ● Introduction 399 ● Immunity a

  • Page 412 and 413:

    Key points Antigen recognition Expr

  • Page 414 and 415:

    Table 50.1: Novel anti-proliferativ

  • Page 416 and 417:

    Key points Treatment of anaphylacti

  • Page 418 and 419:

    DRUGS THAT ENHANCE IMMUNE SYSTEM FU

  • Page 420 and 421:

    PART XII THE SKIN

  • Page 422 and 423:

    ● Introduction 411 ● Acne 411

  • Page 424 and 425:

    DERMATITIS (ECZEMA) PRINCIPLES OF T

  • Page 426 and 427:

    SPECIALISTS ONLY SPECIALISTS ONLY E

  • Page 428 and 429:

    TREATMENT OF OTHER SKIN INFECTIONS

  • Page 430 and 431:

    effect of too high a dose of UVB in

  • Page 432 and 433:

    PART XIII THE EYE

  • Page 434 and 435:

    ● Introduction: ocular anatomy, p

  • Page 436 and 437:

    to cause pupillary dilatation, name

  • Page 438 and 439:

    Table 52.3: Antibacterial agents us

  • Page 440 and 441:

    Table 52.6: Common drug-induced pro

  • Page 442 and 443:

    PART XIV CLINICAL TOXICOLOGY

  • Page 444 and 445:

    ● Introduction 433 ● Pathophysi

  • Page 446 and 447:

    Table 53.2: Central nervous system

  • Page 448 and 449:

    which provide anonymized data to th

  • Page 450 and 451:

    Peak plasma levels after smoking ci

  • Page 452 and 453:

    Key points Acute effects of alcohol

  • Page 454 and 455:

    FURTHER READING Goldman D, Oroszi G

  • Page 456 and 457:

    Table 54.2: Common indications for

  • Page 458 and 459:

    Table 54.5: Antidotes and other spe

  • Page 460 and 461:

    Commission on Human Medicines (CHM)

  • Page 462 and 463:

    Note: Page numbers in italics refer

  • Page 464 and 465:

    atrial fibrillation 217, 221 digoxi

  • Page 466 and 467:

    Cushing’s syndrome 302 cyclic ade

  • Page 468 and 469:

    5-fluorouracil 375-6 fluoxetine, mo

  • Page 470 and 471:

    children 54 diazepam 108 iron prepa

  • Page 472 and 473:

    non-steroidal anti-inflammatory dru

  • Page 474 and 475:

    puberty (male), delay 314 puerperiu

  • Page 476:

    tolerance 9, 433 benzodiazepines 10

A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
World Journal of Gastrointestinal Pharmacology and Therapeutics
World Journal of Gastrointestinal Pharmacology and Therapeutics
World Journal of Gastrointestinal Pharmacology and Therapeutics
World Journal of Gastrointestinal Pharmacology and Therapeutics
World Journal of Gastrointestinal Pharmacology and Therapeutics
Clinical Pharmacology of Sleep
World Journal of Gastrointestinal Pharmacology and Therapeutics
World Journal of Gastrointestinal Pharmacology and Therapeutics
Clinical Pharmacology and Therapeutics
World Journal of Gastrointestinal Pharmacology and Therapeutics
Diagnosis and pharmacological management of Parkinson's - SIGN
Role of Quantitative Clinical Pharmacology in Guiding Drug
An Anatomico-Clinical Overview - Advances in Clinical ...
2012 EDUCATIONAL BOOK - American Society of Clinical Oncology
CLINICAL PHARMACOLOGY AND THERAPEUTICS FOR THE ...
CLINICAL PHARMACOLOGY THERAPEUTICS
Pharmacology and therapeutics, clinical trial - Dermage